Genetic Screening and Testing

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Genetic screening and testing is often recommended for couples who have had multiple failed IVF transfers, reoccurring miscarriage and a known family history of genetic risks. It also enables couples who intend to use donated eggs, to make informed decisions about potential genetic risks prior to donor selection and pregnancy. Donor agencies can provide genetic counseling services so that the IVF doctor and the intended parents fully understand the implications of the genetic information they have.

What is Genetic Counseling?

Genetic counseling does not equal genetic testing. Although many genetic tests are available, not all are useful or necessary in every individual. Genetic counselors help identify which tests, if any, may be most helpful for each particular couple. The goal of genetic counseling is to provide information about the benefits and limitations of those test to help couples make informed decisions.

What is a genetic counselor?

Genetic counselors are health care providers specially trained to review a couple’s medical and family histories to determine the likelihood of a genetic cause for infertility. They work with your providers to answer questions and identify the best management for you. Professional organizations state that an individual with specialized expertise in genetic counseling is essential in the care of individuals seeking infertility treatment.1

How can a genetic counselor help me?

A genetic counselor can help increase the odds to have a healthy baby for some couples. A genetic evaluation can sometimes uncover the reason for infertility which can help identify if there are treatment options available. For example, approximately 20% of male infertility is caused by an underlying genetic issue.2,3 Finding the genetic issue helps identify the most effective treatment options to increase the chance to have a healthy baby.

Here is an example of how a genetic counselor can help:

A young couple has had a history of miscarriage together with the inability to become pregnant otherwise for over a year. They seek genetic counseling to help find the reason for their problems. During their genetic counseling session, their health history, family history and previous medical test results are reviewed. They also talk about the health of other family members and their family members’ experiences with pregnancy. The genetic counselor tells them about the possibility of a genetic cause for their infertility and discusses testing options. The woman pursues testing that identifies a genetic change called a balanced translocation, which is found in approximately 5% of couples with infertility.4

A balanced translocation is a rearrangement in the chromosomes that can cause an increased risk for multiple miscarriages, including miscarriages that can occur prior to the woman even realizing she is pregnant. In addition, there can also be an increased risk to have a baby born with a chromosome abnormality, which can lead to birth defects and developmental delay. The genetic counselor explains all of the risks associated with the balanced translocation as well as the couple’s reproductive options, including preimplantation genetic diagnosis (PGD). Some literature has reported that PGD can reduce miscarriage rate by 70% and increase the take home baby rate by almost 70%.(5) PGD is typically not offered to all couples, but rather those in specific situations such as the one discussed here. Genetic counseling identified PGD as a option for this couple. They were able to use this information to make informed decisions about future pregnancies and medical treatment.

Here is an example of how a genetic counselor’s perspective is important in the genetic testing process:

A young couple has not been able to become pregnant for over 1 ½ years. They have had many doctor visits, medical tests and fertility treatments. As part of this evaluation, they were both found to have a change (also called a variant) in their MTHFR gene. To their frustration, no one has been able to explain what this result is or what to do about it. They were referred for genetic counseling for further information. During the genetic counseling visit, the counselor was able to review this result in light of the rest of the medical and family history. Ultimately, this MTHFR variant may have implications for their personal and reproductive health, but the exact meaning is unclear. Additionally, given the current understanding of this variant, there is no recommended treatment based on the presence of the variant alone. This type of scenario is common in many genetic tests where there is limited understanding of a particular genetic finding. After this explanation, the couple felt much more informed and wished they had known the limitations of MTHFR testing before they decided to get the test.

How can PGD be used to identify genetic defects in embryos?

Since the time of the first IVF success, scientists and ethicists have understood that the potential of preventing chromosomal and genetic diseases before pregnancy was possible. The process known as pre-implantation genetic diagnosis (PGD) has now been available for over a decade, and the technology has progressed rapidly.

PGD is used to identify genetic defects in embryos created through in vitro fertilization (IVF) before implantation and pregnancy. PGD can be used to select embryos that have less risk of having a genetic disorder, increased chances of resulting in a successful pregnancy, less cancer predisposition, and for sex selection.

There are three basic indications for PGD:
1) aneuploidy screening,
2) translocation analysis, and
3) single gene disorders.
In all cases, a woman goes through the whole IVF process, including ovarian stimulation, egg retrieval, and fertilization. However, on day three after retrieval, a single cell is removed from the embryo for analysis. If the analysis is good, then the doctor will proceed with an embryo transfer on day five.

How does a PGD test for chromosomal abnormalities in embryos

The most common type of PGD performed is aneuploidy, which tests to see if an embryo has chromosomal abnormalities that result in failed implantation, miscarriages and chromosomal disorders such as Downs Syndrome (an extra copy of the #21 chromosome). The initial technique of looking at chromosomes is called fluorescent in-situ hybridization or FISH. With FISH, special probes are created that uniquely bind to specific chromosomes. When placed under a UV light, the chromosomes can be identified under a microscope by the color they emit. Since the human eye can only discern a certain number of colors, this technique is limited to studying 5-10 chromosomes. The original protocol identified the 10 most common chromosomal abnormalities found in miscarriages.

Limitations of aneuploidy include not detecting a chromosome due to failure to pick up the dye or two chromosomes lying on each other. Another problem that plagues all PGD is called mosaicism – when an early embryo can actually have two groups of cells with different numbers of chromosomes. If one cell shows abnormalities, but the majority of the cells are normal, the embryo may be falsely diagnosed as abnormal.

Over the years, most studies have failed to show a benefit to aneuploidy screening with FISH in either pregnancy rates or miscarriage rates. This is probably due to the limitations mentioned above. For this reason, the American Society for Reproductive Medicine (ASRM) has renamed this process pre-implantation genetic screening (PGS) and is recommending that physicians do not do PGS.

What new advances are there to increase success rates?

Two new techniques have reignited interest in aneuploidy screening. One is called CGH for comparative genomic hybridization. With CGH, fluorescent probes are used too, but here, thousands of probes are used and all 23 chromosomes can be studied. The analysis is not done with the human eye, but with a computer-assisted microarray that allows for the complex analysis.

The second technique is single nucleotide polymorphism or Snp analysis. Each person has unique areas on their chromosomes that can be used for indemnification. Using DNA samples from each parent, all 23 chromosomes can be accurately identified. Snp technology may be slightly more accurate than CGH, but there are no large randomized studies that compare the two, or show that either technique significantly improves implantation rates or lowers miscarriage rates.

Some clinics have been using Snp technology for a few years, and some believe that it does accomplish the two goals of improving implantation rates and lowering miscarriage rates, but comparative trials are still needed to prove it. Women aged 35-40 may benefit from aneuploidy screening to allow selection of a small number of normal embryos, thus reducing the multiple pregnancy potential of transferring several embryos, without compromising success rates. For younger women and egg donors, results with single embryo transfers may be improved. Finally, women with repeat miscarriages may benefit from current aneuploidy screening.

Are there tests to determine implantation errors and miscarriage

The second type of PGD is translocation analysis. Here, one of the parents has a re-arrangement of the chromosomes that leaves him/her normal, but the person has high chance of transmitting an abnormal amount of DNA to the eggs or sperm (gametes). This results in a high rate of infertility, a very high miscarriage rate, and in some cases an increased risk of having a child with abnormal chromosomes. Fortunately, PGD is quite effective at eliminating these risks and helping couples conceive healthy pregnancies.

Finally, the most intriguing and controversial type of PGD is single gene disease prevention. Roughly 1/1000 couples carry recessive genes that give them a 25% chance of having an affected child. Well-known examples are cystic fibrosis, Tay-Sachs, and sickle cell disease. If a couple knows they are carriers, embryos can be tested to prevent pregnancy with affected embryos. For couples who have seen their children die from such conditions, this is a miracle. For some ethicists, there are concerns about the eugenic implications of perception of creating “designer babies.”

What are the benefits and risks of PGD testing?

In conclusion, with all its shortcomings and controversy, PGD is here to stay. PGD for translocations and single genes have been shown to be effective and offer couples new hope of having healthy children and preventing the painful decisions regarding pregnancy termination of affected fetuses. Current methods of aneuploidy screening may improve embryo selection and reduce miscarriages, but controlled studies are still needed to prove this.

To determine if you are a candidate for PGD, talk with your doctor. If you are considering PGD ask your doctor or reproductive endocrinologist about potential risks associated with this technique. Not all disorders can be detected with PGD, and not all clinics utilize PGD resources.